Millions of patients each year undergo surgical procedures and many will develop moderate to severe pain which persists for months and years. Chronic pain after surgery (CPAS) is now recognized as a major public health concern which can have a profound impact on a person's quality of life. Currently, there is no standard medical care provided specifically to treat or prevent CPAS. This is due in part to an incomplete knowledge of the mechanisms responsible for the transition of postoperative pain from an acute phenomenon that resolves after the surgical site heals to a chronic pain state. Recent clinical studies show that impaired descending inhibitory systems may predispose individuals to CPAS. Building on this clinical observation, we developed a novel model of CPAS involving depletion of spinal noradrenergic fibers in rats. Reduction in noradrenergic tone prior to unilateral plantar incision resulted in a prolonged ipsilateral and contralateral mechanical allodynia as well as bilateral microglial and astrocyte activation without effects on baseline nociception. Intriguingly, chronic administration of the 22 adrenergic receptor agonist clenbuterol prevented the prolonged ipsilateral and contralateral mechanical allodynia observed in this model. In Specific Aim 1 of the proposal, we will validate this model by conducting long term assessment of several behavioral measures including spontaneous guarding, mechanical hypersensitivity, and impaired food-reinforced operant responding. The simultaneous evaluation of these behavioral measures will allow identification of the most relevant endpoints for future studies and allow novel analysis to examine within animal relationships between these endpoints. In Specific Aim 2 we will use a combination of in vivo and in vitro pharmacological, immunohistochemical, and biochemical methods to examine the mechanisms by which reduced noradrenergic tone contributes to enhanced mechanical hypersensitivity and glial activation following surgical incision. In Aim 3, we will build on preliminary data demonstrating a protective effect of clenbuterol by determining the site of action of this compound as well as the appropriate timing of therapy to prevent or reverse pain related behaviors in this model. Our long term objective is to use this model to begin to identify key cellular mechanisms responsible for the transition from acute to chronic pain following surgery and use this information to identify novel therapeutic strategies that can be rapidly translated into the clinic. PUBLIC HEALTH RELEVANCE: Chronic pain after surgery occurs in a significant percentage of patients following surgical procedures and can have an enormous impact on society in terms of human suffering as well as economic burden due to decreased productivity. The results of these studies will aid in the identification of novel therapeutic approaches to prevent chronic pain after surgery that can be rapidly translated into the clinic.